The Role of interleukin-1 alpha in age-related cerebrovascular senescence in stroke

Details

Stroke is a major cause of death and disability, costing over £6 billion per annum in the UK. A key event during stroke pathogenesis is inflammation regulated by the cytokine interleukin-1 (IL-1) that contributes to brain injury and poor outcome. The IL-1 family of cytokine is composed of two agonists, IL-1alpha (IL-1α) and IL-1beta (IL-1β) and one functional type 1 receptor, but the precise contribution of each IL-1 family members to post-stroke inflammation is unknown. We have recently demonstrated, using new conditional IL-1 genetic mouse models developed by us, that microglial-specific IL-1α is a key regulator of vascular inflammation and repair after stroke. Senescence is an irreversible replicative-arrest state of the cells, leading to dysfunction of surrounding cells, accompanied by expression of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, and IL-8 (referred to as senescence-associated secretory phenotype, SASPs). Senescent cells during ageing promotes tissue inflammation and dysfunction, and is an essential contributor to the progression of age-associated diseases. Importantly, senescence of vascular-related cells contributes to blood–brain barrier dysfunction, a key hallmark of stroke pathogenesis and a risk factor in stroke. The main aim of the project is to investigate new mechanisms of IL-1α-regulated cerebrovascular senescence in stroke, and how those mechanisms could be a risk factor for stroke and key contributors to poor cerebrovascular repair and poor outcomes in aged stroke patients. The project will be conducted within the Brain Inflammation Group, School of Biological Sciences, University of Manchester. The group uses an interdisciplinary approach to understand mechanisms of neuroinflammation in brain disease and is a world leader in the field. The project will use a very large range of cutting-edge state-of-the-art models of brain injury, analytical techniques from molecular/cellular biology to powerful brain imaging techniques and behavioural tests.

Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in Neuroscience or Biomedical Sciences. Research experience in cell cultures, in vivo animal models of disease and basic analytical techniques is desirable.

Eligibility 

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Neuroscience Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

References

– Barrington J, Rivers-Auty J, Strangward P, Tamburrano S, Lénárt N, Swanton T, Lemarchand E, Parry-Jones AR, Dénes Á, Brough D, Allan SM. Interleukin-1 regulates myeloid cell trafficking and cerebral blood flow following intracerebral haemorrhage. Dis Model Mech. 2025 Oct 1;18

– Lemarchand E, Grayston A, Wong R, Rogers M, Ouvrier B, Llewellyn B, Webb F, Lénárt N, Dénes Á, Brough D, Allan SM, Bix GJ, Pinteaux E. Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but may regulate neurorepair processes after experimental ischemic stroke. J Cereb Blood Flow Metab. 2025 Aug;45(8):1479-1492.

– Wong R, Smith CJ, Allan SM, Pinteaux E. Preconditioning with interleukin-1 alpha is required for the neuroprotective properties of mesenchymal stem cells after ischemic stroke in mice. J Cereb Blood Flow Metab. 2023 Dec;43(12):2040-2048.

– Taylor JL, Pritchard HAT, Walsh KR, Strangward P, White C, Hill-Eubanks D, Alakrawi M, Hennig GW, Allan SM, Nelson MT, Greenstein AS. Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2204581119.

– South K, Saleh O, Lemarchand E, Coutts G, Smith CJ, Schiessl I, Allan SM. Robust thrombolytic and anti-inflammatory action of a constitutively active ADAMTS13 variant in murine stroke models. Blood. 2022 Mar 10;139(10):1575-1587.